The present study will test the hypothesis that estrogen has a major role in programming the proliferation and/or morphological differentiation of cytotrophoblasts and growth of the placenta during baboon pregnancy through developmental regulation, in an autocrine/paracrine manner, of expression and production of IGF- lI/IGFBP-2, EGF/EGF receptor. Ontogenetic regulation of trophoblast proliferation/ morphological differentiation and growth factor expression will be determined in placentas obtained from baboons on days 45, 60 and 100 of gestation (term = 184 days). The role of estrogen on the same parameters will be studied in placentas obtained from baboons in which estrogen levels have been prematurely elevated early in pregnancy. The temporal effect of estrogen on peptide growth factor expression and trophoblast proliferation/morphological differentiation will be determined in short-term studies (24 and 48 h after injection of androstenedione to baboons on day 45 of pregnancy). Trophoblast proliferation will be assessed by PCNA (index of DNA replication), and morphological differentiation will be assessed by histology and CS production. Quantification and localization of mRNAs and proteins for IGF-II/IGFBP-2, EGF/EGF receptor will be determined by RT-PCR/Northern/Western blot and in situ hybridization, respectively. The proposed study is expected to provide new insight into the developmental regulation of placental growth and differentiation during early primate pregnancy.